False metabolite

These rules help to avoid incorrect reporting of false metabolites and unnecessary reporting of minor metabolites. Typically, we report metabolites by showing the relative responses of the metabolite and dosed compound on the same graph because the y axis of this graph is labeled relative response (as opposed to concentration units), we alert the recipient that the concentration responses of dosed compound and metabolite may vary. Figure 7.5 is an example of this type of report. 

In fact, sulphanilamdie gives rise to a false metabolite that eventually prevents its ultimate conversion to tetrahydrofolic acid (THFA) as shown below ... 

In a few strains of bacteria, however, the picture is somewhat more complex. Here, sulfonamides are attached to the dihydropteroate diphosphate in the place of the normal PABA. The resulting unnatural product, however, is not capable of undergoing the next necessary reaction (condensation with glutamic acid). This false metabolite... 

Fig. 38.3. Microbial biosynthetic pathway leading to tetrahydrofolic acid synthesis and major site of action ( ) of sulfonamides as well as site of action seen in some bacteria <-) resulting in incorporation of sulfonamide as a false metabolite.

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

The chromogen is often not completely specific, and metabolites and drugs may give falsely elevated results. 

Pretreatment of hair samples also includes an extraction, usually with an alkaline sodium hydroxide solution, followed by cleaning up with LLE with n-hexane/ethyl acetate. Instead of LLE, the employment of SPE is also possible. Furthermore, the solid phase microextraction (SPME) in combination with head-space analysis is usable [104-106]. In the case of using hair samples, possible external contamination (e.g., by passive smoking of Cannabis) has to be considered as false positive result. False positive results can be avoided by washing of the hair samples previous to extraction [107]. Storage of collected samples is another important fact that can cause false results in their content of A9-THC and metabolites [108-110]. 

Structurally related compounds may cross-react with the antibody, yielding inaccurate results. In screening for the herbicide alachlor in well water by immunoassay, a number of false positives were reported when compared with gas chromatography (GC) analysis. A metabolite of alachlor was found to be present in the samples and it was subsequently determined that the cross-reactivity by this metabolite accounted for the false-positive results. On the other hand, cross-reactivity by certain structural analogs may not be an issue. For example, in an assay for the herbicide atrazine, cross-reactivity by propazine is 196% because of atrazine and propazine field use... 

Fluorouracil (5-FU) acts as a false pyrimidine, inhibiting the formation of the DNA base thymidine.26,35 The main mechanism by which it accomplishes this is by inhibiting the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. 5-FU first must be metabolized to its active metabolite (F-dUMP). Additionally, metabolites of 5-FU may incorporate into RNA, inhibiting its synthesis. 

Data-dependent acquisition ability has been developed and incorporated into most software packages [MetaboLynx, Xcalibur, and Analyst Information Dependent Acquisition (IDA)]. In data-dependent acquisition mode, a mass spectrometer decides on the fly whether to collect MS/MS or MSn data, remain in full scan MS mode, or conduct other survey scans based upon user-defined criteria. Product ion spectra of potential metabolites can be automatically acquired in a single LC/ MS run. However, false positives may be generated due to highly intense matrix ion signals that may inadvertently trigger MS/MS or MSn scan functions. 

Both of these are false—Rohypnol pills are often crushed by dealers into a powder, and this powder may contain many contaminants incorporated by drug dealers. In addition, advances in medical technology can now detect Rohypnol metabolites in bodily fluids for 2-3 days after taking the drug. 

ACE inhibitors, such as captopril and enalaprilat, the active metabolite of enalapril, occupy the enzyme as false substrates. Affinity significantly influences efficacy and rate of elimination. 

In addition, because they are stractural analogs of natural substances, antimetabolites can act not only by being introduced into the metabolic process and form false nonfunctional metabolites, but also by inhibiting catalytic functions of certain enzymes or enzyme systems. 

Drug/Lab test interactions A metabolite of tolbutamide in the urine may give a false-positive reaction for albumin if measured by the acidification-after-boiling test. 

Drug/Lab test interactions A labetalol metabolite may falsely increase urinary catecholamine levels when measured by a nonspecific trihydroxyindole reaction. Drug/Food interactions Food may increase bioavailability of the drug. 

Drug/Lab fesf/nferacf/ons Valproic acid is partially eliminated in the urine as a keto-metabolite, which may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproic acid. 

Methyldopa is an false substrate for the dopamine-/ -hydroxylase resulting in a-methylnor-adrenaline. This metabolite is an a2-adrenoceptor agonist an induce, like clonidine, a centrally mediated reduction of sympathetic tonus. 

Reporting false-positive results may send an innocent person to prison, so everything possible must be done to avoid such an outcome. Assays with enhanced sensitivity to detect both parent compound and metabolites will allow for detection of drugs over longer periods of time and for more accurate determination of when an individual was first exposed to a chemical. 

Important intraspecies differences are found in the relative proportions of MAO-A or MAO-B in tissues [e.g., human brain has more MAO-B (about 70%) activity rat brain has more MAO-A]. After administration of an MAOI, intracellular levels of endogenous amines (e.g., NE) increase, but levels of amines not usually found in humans (tryptamine and phenylethylamine) also increase, followed by a compensatory decrease in amine synthesis because of feedback mechanisms. Levels of other amines or their metabolites (i.e., false transmitters) increase in storage vesicles and may displace true transmitters, while presynaptic neuronal firing rates decrease. After 3 to 6 weeks, brain serotonin may return to normal levels and NE levels may decrease. There is a compensatory decrease in the number of receptors, including b-adrenergic receptor-related functions (e.g., NE-stimulated adenyl cyclase). 

One pharmacological theory of the mechanism underlying postural hypotension is the false-transmitter theory. Tyramine may be metabolized to an inactive metabolite (octopamine) that partially fills the NE storage vesicles with a false (inactive) transmitter, but definitive proof is lacking. 

Methenamine mandelate, 1 g four times daily, or methen-amine hippurate, 1 g twice daily by mouth (children, 50 mg/kg/d or 30 mg/kg/d, respectively), is used only as a urinary antiseptic to suppress, not treat, urinary tract infection. Acidifying agents (eg, ascorbic acid, 4-12 g/d) may be given to lower urinary pH below 5.5. Sulfonamides should not be given at the same time because they may form an insoluble compound with the formaldehyde released by methenamine. Persons taking methenamine mandelate may exhibit falsely elevated tests for catecholamine metabolites. 

The urine sample used should be at neutral pH. If the sample has been preserved with acid, a false positive may occur. Drugs such as N-acetylcysteine, 2-mercapto-ethanesulfonate, 2-mercaptopropionylglycine, captopril, penicillamine, and large amounts of synthetic penicillin metabolites and acetoacetate will give positive results. Bacterial contamination may also give a false positive. 

Ketone False positive results may occur in highly pigmented samples, samples containing levodopa metabolites, or samples containing significant amounts of sulfhydryls. 

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